A.(+)-(1R,2R)-1-Phenylcyclohexane-cis-1,2-diol
(2). A 3-L flask with a mechanical stirrer,
thermometer and an inlet port open to
the atmosphere is charged with 375 mL of water. Stirring is started and the following
reagents are added in the order indicated through a powder funnel:
potassium ferricyanide (247 g,
0.75 mol, 3 equiv), anhydrous potassium
carbonate (104 g, 0.75 mol, 3 equiv),
methanesulfonamide (23.8 g,
0.25 mol, 1 equiv), potassium
osmate dihydrate (46.1 mg, 0.125 mmol, 0.05
mol %), (DHQD)2PHAL [1,4-bis(9-O-dihydroquinidinyl)phthalazine,
486.9 mg, 0.625 mmol, 0.25 mol %], 1-phenylcyclohexene (1, 39.55 g,
0.25 mol) and tert-butyl
alcohol (250 mL) (Notes 1 and 2). The slurry is stirred
vigorously for 2 days at a rate of 500 rpm. During this time, the product crystallizes
in the top organic phase, beginning after 4 hr. Also, the appearance of the slurry
gradually changes from a mixture containing red granules (ferricyanide) to yellow
flakes, which are presumably a salt of iron(II).

After the reaction is complete the mixture is treated with ethyl
acetate (250 mL) with stirring to dissolve
the product. The resulting mixture is filtered through a 500-mL medium-fritted
glass funnel and the flask and filter cake are washed with ethyl
acetate (3 × 50 mL). The filtrate is transferred
to a 2-L separatory funnel and the brown-colored aqueous phase
is separated. The organic phase is washed with 2 M potassium
hydroxide (KOH, 2 × 50 mL) with vigorous shaking
to remove methanesulfonamide,
then dried over magnesium sulfate (MgSO4,
12.5 g). The solid is filtered, the cake is washed with ethyl acetate (2 × 37 mL)
and the filtrate is evaporated, to afford a white solid. After the crude product is
dried under reduced pressure overnight, it weighs 47.44
g (99%) (Notes 3 and 4).

B.(−)-(1R,2S)-trans-2-Phenyl-1-cyclohexanol
(3). A 1-L, three-necked flask is set up with a mechanical
stirrer, thermometer, reflux condenser
and nitrogen line. The flask is placed in a silicone
oil bath (230 × 100-mm Schott crystallizing dish). The flask is charged
with a slurry containing activated W-2 Raney nickel
(257.5 g) in wet ethanol
(70% v/v) through a powder funnel
under a blanket of nitrogen. Caution-Fire Hazard! Raney nickel
is extremely pyrophoric when dry and must be kept submerged under liquid at all times
(Note 5). This is done by transferring an aqueous slurry of Raney nickel to the flask with the
aid of
250 mL of anhydrous ethanol
in portions, making sure that the catalyst does not dry. The crude diol from the previous
step is added to the flask, using another
50 mL
of anhydrous ethanol to complete the transfer. The
mixture is stirred vigorously and refluxed for 2 hr (Note 6).

The reaction mixture is allowed to cool to 40-50°C and filtered through a 1/2"-layer
of Celite in a 500-mL fritted (medium) glass funnel, making
sure that the liquid level does not fall below the surface of the filter cake. A total
of
300 mL of ethanol
in small portions is used to transfer the slurry quantitatively to the funnel and
to wash the filter cake. A 170-mm × 90-mm crystallizing dish
is useful to cover the top of funnel during the filtration; however it is not necessary.
The Raney nickel sludge
is transferred with water to a waste container.

The filtrate is concentrated under reduced pressure to remove most of the ethanol
and the resulting two-phase mixture is diluted with
50
mL of saturated brine and extracted with ethyl
acetate (2 × 50 mL). The organic phase is dried
over MgSO4 (3.75 g), filtered
and evaporated under reduced pressure overnight to give the crude alcohol (35.53 g, 94.0%
ee). The solid residue is crystallized from
75 mL
of warm petroleum ether (bp 30-60°C). The crystallization is allowed to
proceed for 3 hr at room temperature and 1 hr at 0°C. The crystalline mass is triturated
with
25 mL of cold (0°C) pentane
to break up the lumps. The slurry is filtered, washed with chilled
pentane in portions (3 × 12.5 mL)
and the solid is dried under reduced pressure overnight to constant weight, to afford
25.12 g (58% from 1) of colorless crystals, mp 64-65°C. The enantiomeric purity was found to be >99.5%
ee by chiral stationary phase SFC (supercritical-fluid chromatography) (Notes 7-8).

2.
The temperature did not rise more than a few degrees above room
temperature after all the reagents were added.

3.
This material, which is contaminated with the chiral ligand, is
sufficiently pure to be used in the next step. A small portion of the crude diol (479 mg) was purified by column chromatography
(SiO2, 30 × 160 mm, 4/1
hexane/
ethyl acetate) to yield a white solid (430 mg, 90%).
The enantiomeric purity of the crude product was determined to be 99.4% ee by SFC
analysis on a chiral stationary phase using a Berger Supercritical Fluid Chromatograph
(Berger Instruments, Newark, DE). The diols were separated using an (R,R) Whelk-O,
250 mm × 4.6 mm, 5μ, 100 Å column at 40°C. Methanol
was used as the modifier and held isocratically at 15% in CO2. The eluent
flow rate was maintained at 2.0 mL/min and the outlet pressure was isobaric at 150
bar (112,500mm, 11.3 × 104mm). All samples were prepared in methanol
at concentrations of 1 mg/mL. The retention time for the diol
peaks were 3.55 min for the (+)-isomer (2) and 3.05 min for the (−)-isomer.
The enantiomeric purity of the crude product was also analyzed by HPLC using an (R.R)
Whelk-O, 250 mm × 4.6 mm, 5μ, 100 Å column at 150 bar (112, 500mm). Isopropyl
alcohol was used as the modifier and held isocratically at 15%
in hexane. The eluent flow
rate was maintained at 1.3 mL/min, and the retention time for the diol peaks were
7.56 min for the (+)-isomer (2) and 5.30 min for the (−)-isomer.

The (−)-enantiomer was prepared using this procedure with (DHQ)2PHAL
as the chiral ligand. The yield of the crude diol, (−)-(1S,2S)-1-phenylcyclohexane-cis-1,2-diol,
was 47.39 g (99%). The enantiomeric purity of this material was found
to be 98.9% ee by CSP-SFC (see Note 4 for
data). These levels of asymmetric induction are similar to those reported by Sharpless
and co-workers, i.e., 99% ee for the (R,R)-isomer using AD-mix-β
[containing (DHQD)2PHAL] and 97% ee for the (S,S)-isomer
using AD-mix-α [containing (DHQ)2PHAL].2

4.
The diol was further purified by recrystallization from ethyl acetate and petroleum ether in
62% recovery. The (+)-(1R,2R)-1-phenylcyclohexane-cis-1,2-diol
thus obtained had a mp of 122-123°C
(lit. mp 121-122°C)3
and was found to have an optical purity of >99.5% ee by chiral SFC. The following
physical data was observed:

5.
The Raney nickel
(WR Grace Grade 28) was obtained as a 50 wt% aqueous slurry from
Strem Chemicals Inc.
The mass of the Raney
nickel was determined by the following procedure:4 The
weight, in grams, of a 500-mL volumetric flask filled with
deionized water was recorded (Mass A). A portion of the water was removed and replaced
with the Raney Nickel slurry.
The remaining volume was filled with deionized water and reweighed (Mass B). The amount
of Raney nickel, in grams,
was calculated using the equation Amt. = 1.167(Mass B − Mass A), where 1.167
accounts for the volume of water displaced by the Raney
nickel catalyst with an average density of 7.00 g/mL.
However, prior to transferring to the flask, the excess water was decanted from the
material. Small spills of Raney nickel slurry were transferred
with a wet Kimwipe to a waste container containing water. The ethanol
was undenatured.

6.
The progress of the reaction may be followed by TLC using 1:3
ethyl acetate/petroleum ether
and visualization with anisaldehyde stain. The diol appears at
an Rf = ≈0.3 (stains olive-brown); the 2-phenylcyclohexanol
appears at an Rf = ≈0.6 (stains blue). The checkers found
that the use of a needle outlet at the top of the condenser helped to maintain a smooth
reflux and prevented leakage though the stirring assembly.

7.
The enantiomeric purity was determined by CSP-SFC (Note 3).
Samples were run isocratically at 1% methanol-modified CO2
and the flow rate was held constant at 4.2 mL/min. Outlet pressure was isobaric at
150 bar (112,500mm, 11.3 × 104mm). All samples were prepared in methanol at concentrations of 1 mg/mL
.
The retention times for the enantiomers were 4.50 min for the (−)-isomer and
3.91 min for the (+)-isomer. The enantiomeric purity of the alcohol was also analyzed
by HPLC using an (R.R) Whelk-O, 250 mm × 4.6 mm, 5μ, 100 Å column. Isopropyl
alcohol was used as the modifier and held isocratically at 2% in hexane. The eluent flow rate was maintained
at 1.3 mL/min, and the retention times for the diol peaks were 14.05 min for the (−)-isomer
(3) and 11.46 min for the (+)-isomer.

Sublimation of a small portion of the alcohol (501
mg) at 45°C (0.05 mm) provided a white powder (467 mg, 93%),
which was found to be analytically pure. The following physical data were observed:

A second batch of product was obtained by concentration and recrystallization of
the mother liquor to provide another 1.89
g (4.4%) of (−)-(1R,2S)-trans-2-phenyl-1-cyclohexanol
of a slightly lower enantiomeric purity (98.6% ee).

8.
The other enantiomer, (+)-(1S,2R)-trans-2-phenylcyclohexanol,
was also prepared by this procedure. The crude mass of the alcohol was 39.15 g (95.8% ee), while after recrystallization, the yield
was 29.80 g (69%) of material with the following properties: mp 64-66°C, >99.5% ee (see Note 7 for data). The reaction appears to be scaleable since
the submitters reported obtaining a 69%
overall yield (122 g) of the (−)
isomer from 1 when this procedure was carried out on a 1-mol scale.

Handling and Disposal of Hazardous Chemicals

The procedures in this article are intended for use only by persons with prior training in experimental organic chemistry. All hazardous materials should be handled using the standard procedures for work with chemicals described in references such as "Prudent Practices in the Laboratory" (The National Academies Press, Washington, D.C., 2011 www.nap.edu). All chemical waste should be disposed of in accordance with local regulations. For general guidelines for the management of chemical waste, see Chapter 8 of Prudent Practices.

These procedures must be conducted at one's own risk. Organic Syntheses, Inc., its Editors, and its Board of Directors do not warrant or guarantee the safety of individuals using these procedures and hereby disclaim any liability for any injuries or damages claimed to have resulted from or related in any way to the procedures herein.

3. Discussion

Enantiomerically pure trans-2-phenylcyclohexanol, first used
by Whitesell as a chiral auxiliary5
has become a popular reagent in a number of asymmetric transformations.6 Some recent applications include asymmetric
azo-ene reactions,7 [4 + 2]-cycloaddition reactions,8
ketene-olefin [2 + 2]-reactions,9
enolate-imine cyclocondensations,10 Pauson-Khand reactions,11palladium
annulations12
and Reformatsky reactions.13 Despite its potential, use of this chiral
auxiliary on a preparative scale is currently limited by its prohibitive cost.

A previous Organic Synthesis procedure employing Whitesell's method affords
both enantiomers of trans-2-phenylcyclohexanol in 3-4 steps from
cyclohexene oxide via a lipase-catalyzed hydrolysis of the corresponding
racemic chloroacetate ester.14 A related reaction, the Lipase PS30-catalyzed kinetic
acetylation of the racemic alcohol afforded the enantiomers in excellent yield and
optical purity.15
However, a limitation of both of these procedures is that to obtain one of the enantiomers,
they require chromatographic purification of an intermediate, making scale-up impractical.
The (+)-enantiomer (≥97% ee) has been prepared from 1-phenyl-1-cyclohexene
by hydroboration with IpcBH2, monoisopinocamphenylborane,
but the reaction is slow, resulting in 70% conversion after 7 days at 0°C.16 A
procedure involving ring opening of cyclohexene oxide with phenyllithium
in the presence of a chiral additive has been reported, but the level of asymmetric
induction is modest (47% ee).17
Other methods that have been used recently to prepare this chiral auxiliary involve
enantioselective epoxidation18 and
protonation.19

The preparation described here is a slight modification of a route published by
King and Sharpless3 via the osmium-catalyzed
asymmetric dihydroxylation (AD) reaction of 1-phenyl-1-cyclohexene.2 The major strengths of this process are that either enantiomer
can be prepared in high optical purity (> 99.5% ee) without the need for chromatography.

Some experimentation afforded improvements to the process. For example, in the
case of the AD reaction, both the osmium and chiral concentrations
could be reduced to a level of 0.05 mol % and 0.25 mol %, respectively, or one-fourth
the levels in the commercial AD-mix formulation, without compromising the yield and
enantiomeric excess of the crude product. The volume of liquid was also reduced to
one-fourth of the quantities reported (
1.5 L
of water and 1 L
tert-butyl alcohol
per mole of substrate versus 5 L of water and
5 L
of tert-butyl alcohol per mole of substrate). Under
these conditions the reaction mixture is a slurry, but the potassium ferricyanide
dissolves as it reacts. Reducing the catalyst concentration had the effect of doubling
the reaction time from 1 day to 2 days. Interestingly, a study on the use of reduced
amounts of osmium in the AD reaction of 1-phenyl-1-cyclohexene
concluded that reducing the quantity of osmium by half (to 0.1
mol %), doubled the reaction time without affecting the yield, but that further reductions
in osmium content made the reaction too sluggish to be useful.20

In scaling up this procedure, the biggest improvement in the overall yield was
achieved by omitting the crystallization of the intermediate diol. The trans-2-phenylcyclohexanol,
which forms relatively large crystals, is easier to handle than the diol, which is
a very fluffy powder. Analysis of the final product was carried out by both CSP-HPLC
and CSP-SFC methods.

The procedures on this site are intended for use only by persons with prior training in the field of organic chemistry.
These procedures must be conducted at one's own risk. Organic Syntheses, Inc., its Editors, who act as checkers,
and its Board of Directors do not warrant or guarantee the safety of individuals using these procedures
and hereby disclaim any liability for any injuries or damages claimed to have resulted from or related in any way to the procedures
herein.

I have read and acknowledge that I have training in the field of organic chemistry
and that Organic Syntheses does not warrant or guarantee safety in the use of these procedures.

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